Preparation and Evaluation of Chronic Hindlimb Ischemia of Lewis Rat_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

ANG Shengjia ¹ ,  CHEN Bing ¹ , LUO Tao ¹ , TONG Zhu ¹ , ZHANG Shuwen ² , SHI Xiaolin ³ , XU Qing ³ , ZHANG Bin ¹ , ZHANG Jian. ¹

1. Vascular Department， Xuanwu Hospital， Capital Medical University， Beijing 100034， China;;
2. Regeneration Testing Laboratory， Xuanwu Hospital， Capital Medical University， Beijing 100034， China;;
3. Department of Anatomy Histology and Embryology， Capital Medical University， Beijing 100034， China;

Corresponding author：

CHEN Bing, Email: cbobc99@yahoo.com.cn

Keywords：

Chronic lower limb ischemia; Suture-occluded method; Rat; Animal model

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Objective 　To establish chronic hindlimb ischemia model with suture-occluded method in rats， and then compare the effects of chronic hindlimb ischemia model with acute ischemia model.
Methods 　Models of chronic hindlimb ischemia were established by using suture-occluded femoral artery method. The laser Doppler blood flow analysis and angiography were performed on day 7， 14， 28， 42， and 49 after operation， and then the rats were sacrificed after angiography， respectively， the quadriceps and gastrocnemius of contralateral and ipsilateral （surgical side） were gotten， which were tested by HE staining and α-actin immunohistochemistry staining， and then calculate arteriolar density.　
Results 　There were no lameness and limb necrosis after operation in chronic hindlimb ischemia models. Laser Doppler analysis found that chronic hindlimb ischemia models were still maintained in ischemia state on day 49 after operation compared with acute ischemic models. The resluts of HE staining showed no acute necrosis and muscle fibrosis in chronic hindlimb ischemia model group. Chronic hindlimb ischemia models after operation did not appear obvious lameness and limb necrosis. The arteriolar density of quadriceps femoris on day 7 after operation in chronic hindlimb ischemia models were less than that in acute hindlimb ischemia models （0.015 2 vs. 0.036 4）.
Conclusions 　Compared with the commonly used acute ischemic models， the duration of arterial limb ischemia in chronic hindlimb ischemia rats， which were established by suture-occluded method， is longer and less likely to be affected by the compensatory mechanisms. So suture-occluded method can provide a new animal hindlimb ischemia model for further study of ischemia angiogenesis mechanism and treatment of severe lower extremity ischemia.

Citation： ANG Shengjia,CHEN Bing,LUO Tao,TONG Zhu,ZHANG Shuwen,SHI Xiaolin,XU Qing,ZHANG Bin,ZHANG Jian.. Preparation and Evaluation of Chronic Hindlimb Ischemia of Lewis Rat. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2012, 19(12): 1291-1297. doi: Copy

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2.	van Royen N， Hoefer I， Bottinger M， et al. Local monocytechemoattractant protein-1 therapy increases collateral artery formationin apolipoprotein E-deficient mice but induces systemic monocytic CD11b expression， neointimal formation， and plaque progression[J]. Circ Res， 2003， 92(2)：218-225.
3.	Takeshita S， Tsurumi Y， Couffinahl T， et al. Gene transfer of naked DNA encoding for three isoforms of vascular， endothelial growth factor stimulates collateral development in vivo[J]. Lab Invest， 1996， 75(4)：487-501.
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6.	Shyu KG， Manor O， Magner M， et al. Direct intramuscularinjection of plasmid DNA encoding angiopoietin-1 but notangiopoietin-2 augments revascularization in the rabbit ischemic hindlimb[J]. Circulation， 1998， 98(19)：2081-2087.
7.	Chang DS， Su H， Tang GL， et al. Adeno-associated viral vector-mediated gene transfer of VEGF normalizes skeletal muscleoxygen tension and induces arteriogenesis in ischemic rat hindlimb[J]. Mol Ther， 2003， 7(1)：44-51.
8.	Brevetti LS， Chang DS， Tang GL， et al. Overexpression of endothelial nitric oxide synthase increases skeletal muscle blood flow and oxygenation in severe rat hindlimb ischemia[J]. J Vasc Surg， 2003， 38(4)：820-826.
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11.	Rajagopalan S， Mohler ER 3rd， Lederman RJ， et al. Regional angiogenesis with vascular endothelial growth factor in peripheral arterial disease：a phaseⅡrandomized， double-blind， controlled study of adenoviral delivery of vascular endothelial growth factor121 in patients with disabling intermittent claudication[J].Circulation， 2003， 108(16)：1933-1938.
12.	Pu LQ， Jackson S， Lachapelle KJ， et al. A persistent hindlimb ischemia model in the rabbit[J]. J Invest Surg， 1994， 7(1)：49-60.
13.	Couffinhal T， Silver M， Zheng LP， et al . Mouse model ofangiogenesis[J]. Am J Pathol， 1998， 152(6)：1667-1679.
14.	Ito WD， Arras M， Scholz D， et al. Angiogenesis but not collateral growth is associated with ischemia after femoral artery occlusion[J]. Am J Physiol ， 1997， 273(3 Pt 2)：H1255-H1265.
15.	杨盛家，陈兵，罗涛，等. 大鼠后肢急性缺血模型的构建与评估[J]. 中国普通外科杂志， 2009， 18(6)：580-583.
16.	梁翠宏，田铧，徐蕴，等. 结扎切断法与白芨微粒栓塞法建立大鼠后肢缺血模型效果比较[J]. 山东大学学报， 2007， 45(10)：1008-1015.
17.	Tang GL， Chang DS， Sarkar R， et al. The effect of gradual or acute arterial occlusion on skeletal muscle blood flow， arteriogenesis， and inflammation in rat hindlimb ischemia[J] . J Vasc Surg， 2005， 41(2)：312-320.
18.	Baffour R， Garb JL， Kaufman J， et al. Angiogenic therapy for the chronically ischemic lower limb in a rabbit model[J] . J Surg Res， 2000， 93(2)：219-229.
19.	刘坤，杨琨，罗军，等. 结扎腹主动脉加双侧腹壁阴部动脉在大鼠后肢缺血模型中的应用[J]. 中国普外基础与临床杂志， 2010， 17(3)：258-262.
20.	杨盛家，陈兵，佟铸，等. 应用激光多普勒血流仪对大鼠后肢缺血模型血流动力学的观察[J]. 中国普外基础与临床杂志， 2010， 17(3)：137-140.
21.	Topper JN， Gimbrone MA Jr. Blood flow and vascular gene expression：fluid shear stress as a modulator of endothelial phenotype[J] . Mol Med Today， 1999， 5(1)：40-46.
22.	Garcia-Cardena G， Comander J， Anderson KR， et al. Biomechanical activation of vascular endothelium as a determinant of its functional phenotype[J] . Proc Natl Acad Sci U S A， 2001， 98(8)：4478-4485.
23.	Buschmann IR， Hoefer IE， van Royen N， et al. GM-CSF：a strong arteriogenic factor acting by amplification of monocyte function[J] . Atherosclerosis， 2001， 159(2)：343-356.
24.	van Royen N， Hoefer I， Buschmann I， et al. Effects of local MCP-1 protein therapy on the development of the collateral circulation and atherosclerosis in Watanabe hyperlipidemic rabbits[J]. Cardiovasc Res， 2003， 57(1)：178-185.

1. Schainfeld RM， Isner JM. Critical limb ischemia：nothing to give at the office?[J]. Ann Intern Med， 1999， 130(5)：442-444.
2. van Royen N， Hoefer I， Bottinger M， et al. Local monocytechemoattractant protein-1 therapy increases collateral artery formationin apolipoprotein E-deficient mice but induces systemic monocytic CD11b expression， neointimal formation， and plaque progression[J]. Circ Res， 2003， 92(2)：218-225.
3. Takeshita S， Tsurumi Y， Couffinahl T， et al. Gene transfer of naked DNA encoding for three isoforms of vascular， endothelial growth factor stimulates collateral development in vivo[J]. Lab Invest， 1996， 75(4)：487-501.
4. Taniyama Y， Morishita R， Aoki M， et al. Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat and rabbit hindlimb ischemia models：preclinical study for treatment of peripheral arterial disease[J]. Gene Ther， 2001， 8(3)：181-189.
5. Paek R， Chang DS， Brevetti LS， et al. Correlation of a simple direct measurement of muscle pO2 to a clinical ischemia index and histology in a rat model of chronic severe hindlimb ischemia[J] . J Vasc Surg ， 2002， 36(1)：172-179.
6. Shyu KG， Manor O， Magner M， et al. Direct intramuscularinjection of plasmid DNA encoding angiopoietin-1 but notangiopoietin-2 augments revascularization in the rabbit ischemic hindlimb[J]. Circulation， 1998， 98(19)：2081-2087.
7. Chang DS， Su H， Tang GL， et al. Adeno-associated viral vector-mediated gene transfer of VEGF normalizes skeletal muscleoxygen tension and induces arteriogenesis in ischemic rat hindlimb[J]. Mol Ther， 2003， 7(1)：44-51.
8. Brevetti LS， Chang DS， Tang GL， et al. Overexpression of endothelial nitric oxide synthase increases skeletal muscle blood flow and oxygenation in severe rat hindlimb ischemia[J]. J Vasc Surg， 2003， 38(4)：820-826.
9. Lederman RJ， Mendelsohn FO， Anderson RD，?et al. Therapeuticangiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (the TRAFFIC study)：a randomised trial[J]. Lancet， 2002， 359(9323)：2053-2058.
10. Aviles RJ， Annex BH， Lederman RJ， et al. Testing clinical therapeutic angiogenesis using basic fibroblast growth factor (FGF-2)[J]. Br J Pharmacol， 2003， 140(4)：637-646.
11. Rajagopalan S， Mohler ER 3rd， Lederman RJ， et al. Regional angiogenesis with vascular endothelial growth factor in peripheral arterial disease：a phaseⅡrandomized， double-blind， controlled study of adenoviral delivery of vascular endothelial growth factor121 in patients with disabling intermittent claudication[J].Circulation， 2003， 108(16)：1933-1938.
12. Pu LQ， Jackson S， Lachapelle KJ， et al. A persistent hindlimb ischemia model in the rabbit[J]. J Invest Surg， 1994， 7(1)：49-60.
13. Couffinhal T， Silver M， Zheng LP， et al . Mouse model ofangiogenesis[J]. Am J Pathol， 1998， 152(6)：1667-1679.
14. Ito WD， Arras M， Scholz D， et al. Angiogenesis but not collateral growth is associated with ischemia after femoral artery occlusion[J]. Am J Physiol ， 1997， 273(3 Pt 2)：H1255-H1265.
15. 杨盛家，陈兵，罗涛，等. 大鼠后肢急性缺血模型的构建与评估[J]. 中国普通外科杂志， 2009， 18(6)：580-583.
16. 梁翠宏，田铧，徐蕴，等. 结扎切断法与白芨微粒栓塞法建立大鼠后肢缺血模型效果比较[J]. 山东大学学报， 2007， 45(10)：1008-1015.
17. Tang GL， Chang DS， Sarkar R， et al. The effect of gradual or acute arterial occlusion on skeletal muscle blood flow， arteriogenesis， and inflammation in rat hindlimb ischemia[J] . J Vasc Surg， 2005， 41(2)：312-320.
18. Baffour R， Garb JL， Kaufman J， et al. Angiogenic therapy for the chronically ischemic lower limb in a rabbit model[J] . J Surg Res， 2000， 93(2)：219-229.
19. 刘坤，杨琨，罗军，等. 结扎腹主动脉加双侧腹壁阴部动脉在大鼠后肢缺血模型中的应用[J]. 中国普外基础与临床杂志， 2010， 17(3)：258-262.
20. 杨盛家，陈兵，佟铸，等. 应用激光多普勒血流仪对大鼠后肢缺血模型血流动力学的观察[J]. 中国普外基础与临床杂志， 2010， 17(3)：137-140.
21. Topper JN， Gimbrone MA Jr. Blood flow and vascular gene expression：fluid shear stress as a modulator of endothelial phenotype[J] . Mol Med Today， 1999， 5(1)：40-46.
22. Garcia-Cardena G， Comander J， Anderson KR， et al. Biomechanical activation of vascular endothelium as a determinant of its functional phenotype[J] . Proc Natl Acad Sci U S A， 2001， 98(8)：4478-4485.
23. Buschmann IR， Hoefer IE， van Royen N， et al. GM-CSF：a strong arteriogenic factor acting by amplification of monocyte function[J] . Atherosclerosis， 2001， 159(2)：343-356.
24. van Royen N， Hoefer I， Buschmann I， et al. Effects of local MCP-1 protein therapy on the development of the collateral circulation and atherosclerosis in Watanabe hyperlipidemic rabbits[J]. Cardiovasc Res， 2003， 57(1)：178-185.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Preparation and Evaluation of Chronic Hindlimb Ischemia of Lewis Rat

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